This invention relates to compounds which are antagonists of the progesterone receptor, their preparation and utility.
Intracellular receptors (IR) form a class of structurally related gene regulators known as xe2x80x9cligand dependent transcription factorsxe2x80x9d (R. M. Evans, Science, 240, 889, 1988). The steroid receptor family is a subset of the IR family, including progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR).
The natural hormone, or ligand, for the PR is the steroid progesterone, but synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, have been made which also serve as ligands. Once a ligand is present in the fluid surrounding a cell, it passes through the membrane via passive diffusion, and binds to the IR to create a receptor/ligand complex. This complex binds to specific gene promoters present in the cell""s DNA. Once bound to the DNA the complex modulates the production of mRNA and protein encoded by that gene.
A compound that binds to an IR and mimics the action of the natural hormone is termed an agonist, whilst a compound which inhibits the effect of the hormone is an antagonist.
PR antagonists may be used in contraception. In this context they may be administered alone (Ulmann, et al, Ann. N.Y. Acad. Sci., 261, 248, 1995), in combination with a PR agonist (Kekkonen, et al, Fertility and Sterility, 60, 610, 1993) or in combination with a partial ER antagonist such as tamoxifen (WO 96/19997, published Jul. 4, 1996).
PR antagonists may also be useful for the treatment of hormone dependent breast cancers (Horwitz, et al, Horm. Cancer, 283, pub: Birkhaeuser, Boston, Mass., ed. Vedeckis) as well as uterine and ovarian cancers. PR antagonists may also be useful for the treatment of non-malignant chronic conditions such as fibroids (Murphy, et al, J. Clin. Endo. Metab., 76, 513, 1993) and endometriosis (Kettel, et al, Fertility and Sterility, 56, 402, 1991). PR antagonists may further be useful in hormone replacement therapy for post menopausal patients in combination with a partial ER antagonist such as tamoxifen (U.S. Pat. No. 5,719,136). PR antagonists, such as mifepristone and onapristone, have been shown to be effective in a model of hormone dependent prostate cancer, which may indicate their utility in the treatment of this condition in men (Michna, et al, Ann. N.Y. Acad. Sci., 761, 224, 1995).
Jones, et al, (U.S. Pat. No. 5,688,810) describe the PR antagonist dihydroquinoline A. 
Jones, et al, described the enol ether B (U.S. Pat. No. 5,693,646) as a PR ligand. 
Jones, et al, described compound C (U.S. Pat. No. 5,696,127) as a PR ligand. 
Zhi, et al, described lactones D, E and F as PR antagonists (J. Med. Chem., 41, 291, 1998). 
Zhi, et al, described the ether G as a PR antagonist (J. Med. Chem., 41, 291, 1998). 
Combs, et al., disclosed the amide H as a ligand for the PR (J. Med. Chem., 38, 4880, 1995). 
Perlman, et. al., described the vitamin D analog I as a PR ligand (Tet. Letters, 35, 2295, 1994). 
Hamann, et al, described the PR antagonist J (Ann. N.Y. Acad. Sci., 761, 383, 1995). 
Chen, et at, described the PR antagonist K (Chen, et al, POI-37, 16th Int. Cong. Het. Chem., Montana, 1997). 
Kurihari, et. at., described the PR ligand L (J. Antibiotics, 50, 360, 1997). 
Elliott (Smith Kline Beecham) claimed the generic indoline M as potential endothelin receptor antagonists (WO 94/14434). The patent does not claim indolines and lacks the appropriate 5-aryl substitution, i.e. CN and NO2. 
wherein: R4=H, Ar, R11, OH, 1-5 C alkoxy (opt. substd. by OH, OMe or halogen), xe2x80x94S(O)qR11, N(R6)2, XR11, halogen or NHCOR6; X=(CH2)n, O, NR6 or S(O)q; n=0-6; q=0-2; R6=H or 1-4 C alkyl; R11=1-8 C alkyl, 2-8 C alkenyl or 2-8 C alkynyl (all optionally substituted); Ar=(i) opt. substd. phenyl or benzo-fused gp. of (a) or (b); or (ii) napthyl, indoyl, pyridyl, thienyl, oxazolindyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, pyrrolyl or pyrimidyl, all opt. substd. by one or more R1 or R2 groups. 
The compounds of this invention have been shown to act as competitive inhibitors of progesterone binding to the PR and act as antagonists in functional models, either/or in-vitro and in-vivo. These compounds may be used for contraception, in the treatment and/or prevention of fibroids, including uterine fibroids, endometriosis, breast, uterine, ovarian and prostate cancer, and post menopausal hormone replacement therapy. This invention also particularly relates to methods of using these compounds in the inducement of contraception and the treatment and/or prevention of benign and malignant neoplastic disease. Such diseases may include, without limitation, benign prostatic hypertrophy, carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate, pituitary, meningioma and other hormone-dependent tumors.
Compounds of this invention include compounds of the formula I: 
wherein:
R1 and R2 are chosen independently from H, alkyl, substituted alkyl; OH; O(alkyl); O(substituted alkyl); OAc; aryl; optionally substituted aryl; heteroaryl; optionally substituted heteroaryl; alkylaryl; alkylheteroaryl; 1-propynyl; or 3-propynyl;
or R1 and R2 are joined to form a ring comprising one of the following: xe2x80x94CH2(CH2)nCH2xe2x80x94; xe2x80x94CH2CH2CMe2CH2CH2xe2x80x94; xe2x80x94O(CH2)mCH2xe2x80x94; O(CH2)pOxe2x80x94; xe2x80x94CH2CH2OCH2CH2xe2x80x94; xe2x80x94CH2CH2N(H or alkyl)CH2CH2xe2x80x94;
n is an integer from 0 to 5;
m is an integer from 1 to 4;
p is an integer from 1 to 4;
or R1 and R2 together comprise a double bond to xe2x95x90C(CH3)2; xe2x95x90C(C3-C6 cycloalkyl), xe2x95x90O, or xe2x95x90C(cycloether), wherein cycloether is selected from tetrahydrofuranyl or hexahydropyranyl;
R3 is H, OH, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C6 alkenyl, alkynyl or substituted alkynyl, or CORA;
RA=H, C1 to C3 alkyl, substituted C1 to C3 alkyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl;
R4=H, halogen, CN, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl;
R5 is selected from the groups a), b) or c):
a) R5 is a trisubstituted benzene ring containing the substituents X, Y and Z as shown below: 
X is selected from halogen, OH, CN, C1 to C3 alkyl, substituted C1 to C3 alkyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C, to C3 thioalkyl, substituted C1 to C3 thioalkyl, S(O)alkyl, S(O)2alkyl, C1 to C3 aminoalkyl, substituted C1 to C3 aminoalkyl, NO2, C1 to C3 perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, CORB, OCORB, or NRCCORB;
RB is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl;
RC is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl:
Y and Z are independent substituents taken from the group including H, halogen, CN, NO2, C1 to C3 alkoxy, C1 to C3 alkyl, or C1 to C3 thioalkyl; or
b) R5 is a five or six membered ring with 1, 2, or 3 heteroatoms from the group including O, S, SO, SO2 or NR6 and containing one or two independent substituents from the group including H, halogen, CN, NO2 and C1 to C3 alkyl, C1 to C3 alkoxy, C1 to C3 aminoalkyl, CORD, or NRECORD;
RD is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl;
RE is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
R6 is H or C1 to C3 alkyl; or
c) R5 is an indol-4-yl, indol-7-yl or benzo-2-thiophene moiety, the moiety being optionally substituted by from 1 to 3 substituents selected from halogen, lower alkyl, CN, NO2, lower alkoxy, or CF3; wherein R6 and R7 are independently chosen from H, methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, cyclohexyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
or pharmaceutically acceptable salt thereof.
A preferred set of compounds of this invention is depicted by structure II: 
wherein:
R5 is a disubstituted benzene ring containing the substituents X, and Y as shown below: 
X is selected from halogen, CN, C1 to C3 alkoxy, C1 to C3 alkyl, NO2, C1 to C3 perfluoroalkyl, 5-membered heterocyclic ring containing 1 to 3 heteroatoms, or C1 to C3 thioalkoxy;
Y is a substituent on the 4xe2x80x2 or 5xe2x80x2 position selected from H, halogen, CN, NO2, C1 to C3 alkoxy, C1 to C4 alkyl, or C1 to C3 thioalkyl; or
R5 is a five membered ring having the structure: 
U is O, S, or NR6,
R6 is H, or C1 to C3 alkyl, or C1 to C4 CO2 alkyl;
Xxe2x80x2 is selected from halogen, CN, NO2, C1 to C3 alkyl or C1 to C3 alkoxy;
Yxe2x80x2 is selected from the group H, F, CN, NO2 or C1 to C4 alkyl; or
R5 is a six-membered ring with the structure: 
X1 is N or CX2;
X2 is halogen, CN or NO2;
or pharmaceutically acceptable salt thereof.
The compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry in Formulas I and II, the present invention includes such optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.
The term xe2x80x9calkylxe2x80x9d is used herein to refer to both straight- and branched-chain saturated aliphatic hydrocarbon groups having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms; xe2x80x9calkenylxe2x80x9d is intended to include both straight- and branched-chain alkyl group with 1 or 2 carbon-carbon double bonds and containing 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms; xe2x80x9calkynylxe2x80x9d group is intended to cover both straight- and branched-chain alkyl group with at least 1 or 2 carbon-carbon triple bonds and containing 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms.
The terms xe2x80x9csubstituted alkylxe2x80x9d, xe2x80x9csubstituted alkenylxe2x80x9d, and xe2x80x9csubstituted alkynylxe2x80x9d refer to alkyl, alkenyl, and alkynyl as just described having one or more substituents from the group including halogen, CN, OH, NO2, amino, aryl, heterocyclic, substituted aryl, substituted heterocyclic, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, arylthio. These substituents may be attached to any carbon of alkyl, alkenyl, or alkynyl group provided that the attachment constitutes a stable chemical moiety.
The term xe2x80x9carylxe2x80x9d is used herein to refer to an aromatic system which may be a single ring or multiple aromatic rings fused or linked together as such that at least one part of the fused or linked rings forms the conjugated aromatic system. The aryl groups include but not limited to phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl.
The term xe2x80x9csubstituted arylxe2x80x9d refers to an aryl as just defined having 1 to 4 substituents from the group including halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio.
The term xe2x80x9cheterocyclicxe2x80x9d is used herein to describe a stable 4- to 7-membered monocyclic or a stable multicyclic heterocyclic ring which is saturated, partially unsaturated, or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group including N, O and S atoms. The N and S atoms may be oxidized. The heterocyclic ring also includes any multicyclic ring in which any of above defined heterocyclic rings is fused to an aryl ring. The heterocyclic ring may be attached at any heteroatom or carbon atom provided the resultant structure is chemically stable. Such heterocyclic groups include, for example, tetrahydrofuran, piperidinyl, piperazinyl, 2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, quinolinyl, thienyl, furyl, benzofuranyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and isoquinolinyl.
The term xe2x80x9csubstituted heterocyclicxe2x80x9d is used herein to describe the heterocyclic just defined having 1 to 4 substituents selected from the group which includes halogen, CN, OH, NO2, amino, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio. The term xe2x80x9cthioalkylxe2x80x9d is used herein to refer to the SR group, where R is alkyl or substituted alkyl, containing 1 to 8 carbon atoms. The term xe2x80x9calkoxyxe2x80x9d refers to the OR group, where R is alkyl or substituted alkyl, containing 1 to 8 carbon atoms. The term xe2x80x9caryloxyxe2x80x9d refers to the OR group, where R is aryl or substituted aryl, as defined above. The term xe2x80x9calkylcarbonylxe2x80x9d refers to the RCO group, where R is alkyl or substituted alkyl, containing 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. The term xe2x80x9calkylcarboxyxe2x80x9d indicates the COOR group, where R is alkyl or substituted alkyl, containing 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. The term xe2x80x9caminoalkylxe2x80x9d refers to both secondary and tertiary amines wherein the alkyl or substituted alkyl groups, containing 1 to 8 carbon atoms, which may be either the same or different and the point of attachment is on the nitrogen atom. The term xe2x80x9chalogenxe2x80x9d refers to Cl, Br, F, or I.
The compounds of the present invention can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids or bases. These salts include, but are not limited to, the following salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and, as the case may be, such organic acids as acetic acid, oxalic acid, succinic acid, and maleic acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium in the form of esters, carbamates and other conventional xe2x80x9cpro-drugxe2x80x9d forms, which, when administered in such form, convert to the active moiety in vivo.
This invention includes pharmaceutical compositions comprising one or more compounds of this invention and a pharmaceutically acceptable carrier or excipient. The invention also includes methods of treatment which comprise administering to a mammal a pharmaceutically effective amount of one or more compounds as described above as antagonists of the progesterone receptor.
The progesterone receptor antagonists of this invention, used alone or in combination, can be utilized in methods of contraception and the treatment and/or prevention of benign and malignant neoplastic disease. Specific uses of the compounds and pharmaceutical compositions of invention include the treatment and/or prevention of uterine myometrial fibroids, endometriosis, benign prostatic hypertrophy; carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate, pituitary, meningioma and other hormone-dependent tumors, particularly progesterone-related tumors. Additional uses of the present progesterone receptor antagonists include the synchronization of the estrus in livestock.
When the compounds are employed for the above utilities, they may be combined with one or more pharmaceutically acceptable carriers or excipients, for example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.05 to 5% suspending agent in an isotonic medium. Such pharmaceutical preparations may contain, for example, from about 25 to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight.
The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.5 to about 500 mg/kg of animal body weight, preferably given in divided doses two to four times a day, or in a sustained release form. For most large mammals, the total daily dosage is from about 1 to 100 mg, preferably from about 2 to 80 mg. Dosage forms suitable for internal use comprise from about 0.5 to 500 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
These active compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred.
These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid, polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringe ability exits. It must be stable under conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacterial and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil.
The compounds of this invention can be prepared by the procedures outlined in the Schemes illustrated below:
Typically the compounds of this invention are prepared in a convergent manner as shown is Scheme 1, by a suitable coupling reaction. For example, a palladium mediated coupling of an aryl halide with an aryl boronic acid provides the desired bi-aryl substituted target. The choice of the aryl halide-aryl boronic acid combination is established experimentally. 
As outlined in Scheme 2, the xe2x80x9cright sidexe2x80x9d of the compounds of this invention may be prepared by following the procedure described in Letcher, R. M. et. al., J. Chem. Soc. Perkin Trans., 1: 939-944, 1993. 
As an example, the right side template, 2, is prepared by condensing an appropriately substituted phenyl hydrazine and a suitable ketone to give the corresponding hydrazone. This material is cyclized to an imine in refluxing acetic acid and then reduced to the desired indoline template 2. Examples 1-7 and 10-20 were prepared by this route using the appropriate ketone.
Alternatively the right side template may be prepared as outlined in Scheme 3. The commercially available oxindole is di-alkylated at C-3 by using an appropriate base and the corresponding alkyl halide to give the 3,3-dialkyl-oxindole, 8, or the spiro-cyclic oxindole 9. These oxindoles are then brominated under standard conditions and the carbonyl group is reduced to the desired methylene using a hydride mediated reduction. The timing of the aryl coupling and the reduction of the 2-position carbonyl are established experimentally. 
The right side templates are coupled with an appropriate aryl boronic acid using an appropriate palladium (0) catalyst, Scheme 4. For example compound 10 is coupled under standard Suzuki conditions with an appropriately substituted aryl-boronic acid to afford compound 11. 
The compounds of this invention, are stable semi-solids and are conveniently converted into their corresponding salts by treatment with acid. Example 1, compound 11 (R1=R2=R3=Me), when treated with HCl in dioxane affords the HCl salt (Example 2) as a white solid. The racemic indolines can be separated into their enantiomers by Chiral HPLC, to provide the individual enantiomers in  greater than 98% EE.